Hemodialysis membranes for use in the artificial kidney are at the present time generally made of cellophane materials. The best of these materials currently available for such purpose has been found to be a cellulose regenerated from a cuproammonium solution, plasticized with glycerol and identified by the trademark "Cuprophan". Although Cuprophan membranes provide ultrafiltration rates and clearance of low molecular weight solutes within the desirable ranges for proper hemodialysis, they still have many deficiencies which prevent them from being completely satisfactory as hemodialysis membranes. Certain toxins which it is thought necessary to remove from the blood by hemodialysis are "middle molecules", i.e., molecules of molecular weights in the range of 300 to 5,000. Such middle molecules pass through Cuprophan membranes at rates much slower than is desirable. Babb et al ("The Genesis of the Square Meter-Hour Hypothesis" Trans.ASAIO, Vol.XVII, (1971) p. 81-91) advanced the hypothesis that higher molecular weight metabolites (middle molecules) are important uremic toxins. The blood from normal persons does not show the presence of middle molecules while uremic patients exhibit a significant amount of middle molecules, particularly in the range of 300 to 1,500 molecular weight. In testing Babb's hypothesis, it was found that metabolites having a molecular weight less than 300 or greater than 2,000 were not believed to be causing uremic abnormalities and in fact, metabolites in the 300 to 1,500 molecular weight range were the predominant causes of uremic toxicity and neuropathy. (Babb et al "Hemodialyzer Evaluation By Examination of Solute Molecular Spectra" Trans. ASAIO, Vol XVIII (1972) pg. 98-105). Popovich et al, ("The Prediction of Metabolite Accumulation Concomitant With Remal Insufficiency: The Middle Molecule Anomoly" Trans.ASAIO, Vol XX (1974) p 377-387) discuss the results of numerous clinical investigators who explored the connection of neuropathy to middle molecule concentrations. Additionally, the burst and tear strengths of Cuprophan membranes are lower than is desirable in materials employed in hemodialysis and their shelf-life is low, apparently due to migration of plasticizer during storage. Further, the permeability of the Cuprophan membranes has been found to vary from batch to batch and to decrease on aging. Lastly, it is very difficult to cause adhesion between Cuprophan and other materials and between Cuprophan and itself. Thus, it is difficult to utilize improved hemodialyzer designs requiring leak-proof compartments which depend upon the membrane material for sealing off blood from dialysate solution and blood and dialysate solutions from the atmosphere.
The membranes prepared from the present invention are significantly improved over the state-of-the-art materials, e.g., Cuprophan in the following areas.
1. Polycarbonate membranes permit clearance of critical "middle molecules" up to 4 times greater than Cuprophan in comparable tests while exhibiting an ultrafiltration rate of 1.25 to 2 times Cuprophan membranes. PA1 2. The burst strength of polycarbonate membranes is 1.5-2 times that of Cuprophan. PA1 3. The latitude of membrane properties achievable with polycarbonates is considerable and can be arranged in accordance with clinical needs. PA1 4. Polycarbonate membranes are stiffer than Cuprophan in the wet state. This property results in thinner blood layers in dialyzers, more efficient dialysis and lower blood priming volume. PA1 5. Polycarbonates are heat-sealable wet or dry permitting wide latitude in dialyzer design. PA1 6. Due to greater efficiency of dialysis with polycarbonate membranes projections indicate a greatly reduced dialysis time (9 hrs/wk) compared with Cuprophan. PA1 7. Dialysis procedures using polycarbonate membrane have resulted in the improved physical condition of dialyzed patients including increased hematocrit, decreased blood pressure, improved motor nerve conduction velocity and reduction in symptoms of neuropathy. PA1 8. Polycarbonate membranes are up to 36.6% more compatible with blood than are Cuprophan membranes.
In attempting to develop hemodialysis membranes with mechanical and transport properties superior to those of Cuprophan, it has previously been proposed, by two of the present co-inventors, to fabricate membranes of polyether-polycarbonate block copolymers containing a balance of hydrophobic aromatic polycarbonate blocks, which impart toughness, and hydrophilic polyether blocks, which impart water and solute permeability. The polycarbonate system was chosen for dialysis membrane development because of the outstanding mechanical properties shown by commercial polycarbonate, the very low thrombogenicity exhibited by properly heparinized polycarbonate surfaces, the ease of forming this polymer type into various configurations such as films and fibers, and the many synthetic possibilities for chemical modification of the basic aromatic polycarbonate backbone structure to achieve desired membrane transport properties. As disclosed in the "Proceedings of the 5th Annual Contractors' Converence of the Artificial Kidney Program of the National Institute of Arthritis and Metabolic Diseases", U.S. Department of Health, Education and Welfare (1972), pages 32-33, gelled membranes were prepared from polyether-polycarbonate block copolymers by means of the phase inversion technique, i.e., casting a solution of the copolymer in a suitable solvent onto a substrate surface to form a layer which is allowed to dry only partially and which is then immersed in a liquid gelation medium in which the copolymer is insoluble but which is miscible with the solvent, employing chloroform as the casting solvent and methanol as the gelation medium. The gelled membranes resulting from such procedure, while exhibiting considerable superiority over Cuprophan membranes in their permeabilities to solutes in the middle molecule range, were found, however, to possess several drawbacks to their practical use as hemodialysis membranes. First of all, their ultrafiltration rates were 2 to 5 times that of Cuprophan membranes, which would be clinically unacceptable for hemodialysis as presently administered due to the possibility of dehydration of the patient occurring during treatment. Secondly, their burst strength was no more, and in many cases, less than that of Cuprophan membranes. Thirdly, attempts at continuous casting of the membrane on production-type machinery in widths suitable for use in commercial hemodialyzers, presented further problems which rendered the methanol gelation procedure impractical for commercial hemodialysis membrane production.
The most serious problem encountered was the frequent occurrence of gross leakage of albumin through the membranes during ultrafiltration testing, and which was found to be attributable to holes or other imperfections in the ultrathin surface of the membrane which forms the barrier between the blood and the dialysate or flushing solution. All of these membranes are referred to as being "anisotropic" or "skinned", which means that their two sides are significantly different from each other, one side being relatively smooth and the other side being relatively rough and porous. The smooth side is the "barrier" layer which faces the blood during hemodialysis and is quite thin, on the order of 0.05 to 0.2 microns. The remainder of the membrane merely functions as a support structure and is about 25 to 30 microns in thickness. The integrity of the barrier layer is crucial to the performance of the membrane in dialysis. Any perforation, puncture or other compromise of the integrity of the barrier layer destroys the usefulness of the membrane and all materials in contact with the membrane merely leak through. It has now been proven by electron microscopy that the methanol-gelled polycarbonate membranes are formed with their barrier layers on the side of the membrane contacting the casting surface rather than the side of the membrane facing the air during drying. The significance of this fact is that continuous casting of these membranes on production-type machinery involves continuously peeling the delicate barrier layer off of the casting surface during the process, making it almost impossible to maintain the integrity of the barrier layer and obtain a membrane suitable for use in hemodialysis. Also, it was found that long term exposure of the membrane to methanol affects the membrane properties, thereby necessitating the quick and extensive flushing or washing of the membrane to remove the methanol therefrom and replace it with water in order for the membrane to have adequate shelf-life. One additional problem presented was the impracticality of employing large volumes of methanol as the gelation medium due to the cost, toxicity and flammability of this material.
Membranes of polycarbonate type have been made by other investigators such as suggested in British Patent Specification No. 1,395,530, but these membranes have been found unsuitable for hemodialysis purposes. See also Kesting, J. Macromol, Sci. (Chem), A4(3), pp. 655-664 (1970); U.S. Pat. Nos. 2,964,794, 3,031,328, 3,450,650, 3,526,588 and 3,655,591; and British Patent Specification No. 1,059,945.
It is therefore an object of the present invention to provide hemodialysis membranes having improved permeability to solutes in the middle molecule range as compared with presently available hemodialysis membranes, while maintaining low molecular weight solutes.
Another object of the invention is to provide hemodialysis membranes having improved burst and tear strengths as compared with presently available hemodialysis membranes.
A further object of the invention is to provide hemodialysis membranes having improved shelf-life as compared with presently available hemodialysis membranes. A further object of the present invention is to provide hemodialysis membranes having improved sealability over presently available hemodialysis membranes making possible leak-proof hemodialyzer compartments through simple heat-sealing of the membranes.
Still another object of the invention is to provide a process for producing gelled polycarbonate membranes useful for hemodialysis and having the improved properties as set forth in the preceding objects, which is easily and economically adaptable to large scale machine production without impairing the integrity of the barrier layer of the membrane.